Serum amyloid a induces inflammation, proliferation and cell death in activated hepatic stellate cells

Sören V. Siegmund, Monika Schlosser, Frank A. Schildberg, Ekihiro Seki, Samuele De Minicis, Hiroshi Uchinami, Christian Kuntzen, Percy A. Knolle, Christian P. Strassburg, Robert F. Schwabe

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-Terminal kinase (JNK), Erk and Akt and enhanced NF-κBdependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB-and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.

Original languageEnglish
Article numbere0150893
JournalPLoS ONE
Volume11
Issue number3
DOIs
StatePublished - Mar 2016
Externally publishedYes

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